Project Summary/Abstract This is an application for the Mentored Clinical Scientist Career Development Award (K08) for Dr. Daniel Mordes, an Instructor at Massachusetts General Hospital, Harvard Medical School. This proposal describes a 5-year training program comprised of mentored laboratory research, formal coursework, seminars, and conferences to foster the career development of an academic physician-scientist in the subspecialty of neuropathology. This award will provide the necessary support to establish Dr. Mordes as an independent investigator studying frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). He aims to 1) master current methods using stem cells to model neurological disease, 2) obtain the executive skills to manage an independent translational research laboratory 3) become an expert in the neuropathology of neurodegenerative disease. In order to accomplish these goals, Dr. Mordes has designed a career development plan and assembled a group of accomplished basic scientists and physician- scientists with expertise in stem cell biology, cellular signaling pathways, neurobiology, genome editing, and neurodegenerative disease. The Applicant: Dr. Mordes graduated AOA from the MD/PhD program at Vanderbilt University and has completed clinical training in Neuropathology at Massachusetts General Hospital (MGH). Institutional Environment and Mentor: The training program combines the unique clinical and research resources of MGH with the laboratory of Professor Kevin Eggan, who has a strong track record of mentoring successful independent investigators, at Harvard University. Career Development Plan: Dr. Mordes has assembled a team of senior faculty advisors at MGH and Harvard Medical School to support his career development. His training will include the completion of advanced coursework and technical training at Harvard, HMS, and the Broad Institute, and the presentation of his research at national meetings. Research: Frontotemporal dementia (FTD) is a devastating neurodegenerative disease characterized by severe cognitive impairments and the progressive loss of cortical neurons. There are no disease-modifying treatments approved for FTD. Forms of FTD have shared neuropathological features with amyotrophic lateral sclerosis (ALS), which is a rapidly progressive neuromuscular disorder. The most common genetic cause of ALS and FTD is a hexanucleotide repeat expansion in C9ORF72, which is associated with the production of toxic dipeptide repeat proteins (DPRs). Dr. Mordes has employed new methods of producing human neurons from pluripotent stem cells to establish models of C9ORF72-associated disease. He aims to understand the effects of DPRs in specific neuronal types through a combination of transcriptomics, proteomics, and neuropathological approaches, and to identify novel cellular pathways for the development of candidate treatments. Furthermore, he will determine the effects of a specific nuclear signaling pathway on the neuronal response to DPRs. This research will improve our understanding of ALS and FTD and will help guide the establishment of new, and urgently needed, therapeutic efforts aimed at slowing disease progression.